Clinical Diagnosis

There are no generally accepted diagnostic criteria for CADASIL.

The clinical presentation of CADASIL varies among and within families. The disease is characterized by five main symptoms: migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment.

• Migraine with aura occurs in 20%-40% of individuals with CADASIL. When present, it is the first symptom with a mean age of onset of 30 years (age range 6-48 years). In 50% of cases, atypical attacks occur with prolonged, basilar or hemiplegic aura and confusion, fever, meningitis or coma.
• Transient ischemic attacks and ischemic stroke occur at a mean age of 47 years (age range 20-70 years), in most cases without conventional vascular risk factors. Ischemic event are subcortical and present in most individuals as lacunar syndromes.
• Mood disturbances occur in 20% of affected individuals, with severe depressive episodes.
• Apathy occurs in 40% of individuals and may be independent of depression.
• Cognitive disturbance (dysexecutive syndrome) is progressive, with some preservation of recognition and semantic memory. This occurs as an isolated finding in 10% of affected individuals, but in most there is a concurrent stepwise deterioration with recurrent strokes.

Frequent and diagnostically important signs on brain magnetic resonance imaging (MRI) [Auer et al 2001, O'Sullivan et al 2001]:

• T₂-signal abnormalities in the white matter of the temporal pole
• T₂-signal abnormalities in the external capsule

A family history consistent with autosomal dominant inheritance supports the diagnosis [Dichgans et al 1998, Razvi et al 2005a] but is not required [Joutel et al 2000].

Brain imaging. Imaging abnormalities in CADASIL evolve as the disease progresses [van den Boom et al 2003, Singhal et al 2005, Liem et al 2008a].

• MRI white matter hyperintensities, although sometimes very subtle, are consistently visualized from age 21 years onward [Oberstein 2003].
• In individuals age 20-30 years with a pathogenic mutation, distinctive white matter hyperintensities often first appear in the anterior temporal lobes, when the rest of the white matter, except for periventricular caps, appears unaffected [Oberstein 2003, van den Boom et al 2003].
• In the course of the disease, the load of white matter hyperintensity lesions increases, eventually coalescing to the point where, in some elderly individuals, normal-appearing white matter is barely distinguishable [Chabriat et al 1998].

In symptomatic individuals, white matter hyperintensities are symmetrically distributed and located in the periventricular and deep white matter. Within the white matter, the frontal lobe is the site with the highest lesion load, followed by the temporal and parietal lobes [Chabriat et al 1999, Auer et al 2001, O'Sullivan et al 2001].

Additional findings

• Subcortical lacunar lesions (SLLs). Linearly arranged groups of rounded, circumscribed lesions at the junction of the grey and white matter with signal intensity identical to that of cerebrospinal fluid, SLLs are found in approximately two thirds of affected individuals and may be a specific marker for CADASIL [van den Boom et al 2002].
• Cerebral microbleeds. Located predominantly in the thalamus, cerebral microbleeds are best visualized with T₂*-weighted gradient echo imaging [Lesnik Oberstein et al 2001, Dichgans et al 2002].

Pathology. The diagnosis can be confirmed by ultrastructural analysis of small arterioles obtained, for example, by skin biopsy [Goebel et al 1997, Ruchoux & Maurage 1997]. Electron microscopy shows characteristic granular osmophilic material within the vascular media close to smooth muscle cells. These changes are highly specific for CADASIL but the sensitivity of biopsy is limited and depends on the quality of the sample and skills of the pathologist [Schultz et al 1999].

NOTCH3 immunostaining, a means of confirming the diagnosis, is quite sensitive, specific, and more straightforward than electron microscopy, but is not offered routinely in a diagnostic setting [Joutel et al 2001, Oberstein 2003].

Molecular Genetic Testing

Gene. NOTCH3 is the only gene in which mutations are known to cause CADASIL.

Clinical testing

• Sequence analysis/mutation scanning of entire coding and flanking intronic regions. Most mutations in NOTCH3 in individuals with CADASIL are located in exon 4, followed by exons 3, 5, 6, and 11 [Joutel et al 1997, Oberstein et al 1999, Markus et al 2002, Peters et al 2005a]. Geographic variations have been described, showing exon 3 to be the second most common mutation site in French, British, and German persons [Joutel et al 1997, Markus et al 2002, Peters et al 2005a], while exon 11 frequently harbors mutations in affected Dutch persons [Oberstein 2003].
  
  The mutation detection rate is up to 96% in individuals with well-defined or biopsy-proven CADASIL [Markus et al 2002, Peters et al 2005a].
  
  Note: Possible explanations for the discrepancies between different studies in the location of the mutations and the mutation detection rate include study size, differences in molecular genetic testing methods (mutation scanning analysis vs direct sequence analysis), population differences, including possible founder effects [Mykkanen et al 2004], and different inclusion criteria.

Table 1. Summary of Molecular Genetic Testing Used in CADASIL

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency 1	Test Availability
NOTCH3	Targeted mutation analysis 2	c.397C>T, c.544C>T, c.3206A>G	See footnote 3	Clinical
	Sequence analysis / mutation scanning	Sequence variants 4	Estimated >95% 5
	Sequence analysis of select exons 6	Sequence variants 4	Unknown
	Deletion / duplication analysis 7	Deletion / duplication of an exon(s) or whole gene	Unknown 8

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Mutation panel may vary by laboratory.

3. Detection frequency varies per laboratory depending on the mutations tested and the founder mutations per population/ethnicity.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.

5. When all exons coding for epidermal growth factor-like (EGFL) repeats (see Molecular Genetics) are sequenced (exons 2-23) and stringent inclusion criteria are applied [Markus et al 2002, Peters et al 2005a].

6. Exons sequenced may vary by laboratory.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

8. Boon et al [2009]

Interpretation of test results

• Homozygous mutations have been described in CADASIL [Tuominen et al 2001, Liem et al 2008b]. The phenotype of individuals homozygous for NOTCH3 mutations falls within the CADASIL spectrum.
• For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. For diagnostics, all EGFL-encoding exons (2-23) (see Molecular Genetics) are sequenced.

• Some laboratories perform sequencing of these exons simultaneously; others start with selected exons (e.g., exons 2-6 and 11 followed by complete sequencing of all exons encoding the EGFL repeats).
• If no mutation is identified, deletion/duplication analysis may be considered.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotype is known to be caused by mutations in NOTCH3.

The NOTCH3 signaling pathway plays a role in tumorigenesis (see Molecular Genetics) [Park et al 2008, Yamaguchi et al 2008].

Natural History

CADASIL is a microangiopathy mainly affecting the brain. The presenting symptoms, age at onset, and disease progression in CADASIL vary.

Subcortical ischemic events. Transient ischemic attacks (TIAs) and stroke, the most frequent presentation, are found in approximately 85% of symptomatic individuals [Dichgans et al 1998]. Strokes related to small vessel pathology are clearly the main manifestation of the disease.

Mean age at onset for ischemic episodes is approximately 46 years (age range: ~19-67 years) [Opherk et al 2004].

Ischemic episodes typically present as a classic lacunar syndrome (pure motor stroke, ataxic hemiparesis/dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brain stem or hemispheric) are also observed. Ischemic episodes are often recurrent, leading to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy.

Strokes involving the territory of a large artery have occasionally been reported. However, those observations may be coincidental.

Cognitive deficits and dementia. Cognitive deficits, the second most frequent feature, are observed in approximately 60% of symptomatic individuals. They may start as early as age 35 years. Approximately 75% of affected individuals develop dementia [Dichgans et al 1998, Opherk et al 2004, Dichgans 2009].

The pattern of cognitive dysfunction is characterized by deficits in executive function (timed measures and measures of error monitoring), verbal fluency, and memory with benefit from clues [Peters et al 2005b]. Cognitive dysfunction is accompanied by a narrowing of the field of interest. In most cases, cognitive decline is slowly progressive with additional stepwise deterioration. Amberla et al [2004] observed deterioration of working memory and executive function in individuals with NOTCH3 mutations in the prestroke phase, and infer that cognitive decline may start insidiously before the onset of symptomatic ischemic episodes.

Migraine. Migraine occurs in approximately 35% of individuals with CADASIL, with the first attack occurring at a mean age of 26 years. Ninety percent of individuals with migraine have migraine with aura [Dichgans et al 1998]. In some families with CADASIL, migraine with aura is the most prominent symptom. In 50% of cases atypical attacks occur with prolonged, basilar or hemiplegic aura and confusion, fever, meningitis or coma.

Reversible acute encephalopathy. Acute encephalopathy has been described in some individuals, with confusion, headache, pyrexia, seizures, and coma, sometimes leading to death [Feuerhake et al 2002, Schon et al 2003].

Psychiatric disorders. Thirty percent of individuals with CADASIL experience psychiatric disturbance, varying from personality changes to severe depression [Dichgans et al 1998]. Whether these disturbances are primary or reactive is not yet clear. However, individuals with CADASIL presenting with psychiatric problems have been described [Leyhe et al 2005, Nakamura et al 2005].

Epilepsy. Epilepsy is present in 10% of individuals with CADASIL and presents in middle age [Dichgans et al 1998].

Pregnancy. It has been suggested that during pregnancy, but especially during puerperium (the period between childbirth and the return of the uterus to its normal size), an increased risk for migraine with aura occurs. The symptoms are sometimes confused with transient ischemic symptoms [Roine et al 2005]. See Pregnancy Management.

Other

• Cardiac involvement. Controversy exists as to whether CADASIL is associated with cardiac involvement. In a study from The Netherlands, nearly 25% of individuals with NOTCH3 mutations had a history of acute myocardial infarction (MI) and/or current pathologic Q-waves on electrocardiogram [Lesnik Oberstein et al 2003]. This percentage was significantly higher than in controls without a NOTCH3 mutation. However, another study of 23 individuals with a NOTCH3 mutation found no signs of previous MI on ECG [Cumurciuc et al 2006].
• Subclinical peripheral neuropathy has been reported in some individuals [Schroder et al 2005, Sicurelli et al 2005].
• Ocular findings. Subclinical retinal lesions are reported [Cumurciuc et al 2004]. Fundoscopy may reveal clinically silent retinal vascular abnormalities [Haritoglou et al 2004].

Long-term prognosis and causes of death. Data on the long-term prognosis in CADASIL come from a large study of 411 individuals [Opherk et al 2004]. According to that study the median age at onset of inability to walk without assistance was approximately 60 years and the median age at which individuals became bedridden was 64 years. The median age at death was 68 years with a more rapid disease progression in men than in women. The median survival time of men was significantly shorter than expected from German life tables, whereas the median survival time of women was not significantly reduced. Pneumonia was the most frequent cause of death, followed by sudden unexpected death and asphyxia. At onset of the cause of death, 78% of individuals were completely dependent and 63% were confined to bed.

Pathophysiology. Cerebral blood supply in individuals with CADASIL is reduced below demand, as demonstrated by an increased oxygen extraction rate in asymptomatic and demented individuals with CADASIL. Cerebral blood flow, cerebral blood volume, and cerebral glucose utilization are significantly reduced [Chabriat et al 2000, Bruening et al 2001, Pfefferkorn et al 2001]. In addition, cerebral vasoreactivity is impaired, consistent with the observed degeneration of vascular smooth muscle cells in small arteries and arterioles. Increased fragility of cerebral microvessels is suggested by a high frequency of cerebral microbleeds at autopsy and on gradient echo MR images [Dichgans et al 2002].

Genotype-Phenotype Correlations

Although some studies describe phenotype-genotype correlations, the genotype cannot be used to predict the phenotype in individuals with CADASIL [Singhal et al 2004]. Even within a single family, the age of onset, disease severity, and disease progression can vary significantly.

Dichgans et al [1999] found no influence of the NOTCH3 genotype on quantitative MRI variables.

Opherk et al [2004] found the c.350G>T (p.Cys117Phe) mutation associated with a younger age at death and the c.521G>A (p.Cys174Tyr) mutation with a younger age of onset for stroke and death.

Lesnik Oberstein et al [2001] detected an increased number of cerebral microbleeds in individuals with the c.457C>T (p.Arg153Cys) mutation.

Homozygous mutations have been described in CADASIL [Tuominen et al 2001, Liem et al 2008b]. The phenotype of individuals homozygous for NOTCH3 mutations falls within the CADASIL spectrum.

Penetrance

Penetrance of the disease is probably 100%, but expression varies in age of onset, severity of the clinical symptoms, and progression of the disease.

Anticipation

Anticipation, the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, was suggested in a family with a c.539C>G (p.Ser180Cys) mutation reported by Nakamura et al [2005]. No other occurrence of anticipation in persons with CADASIL has been reported.

Nomenclature

Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of CADASIL.

Prevalence

Based on a small registry for CADASIL in the area of Glasgow, Razvi et al [2005b] calculated a mutation frequency of 1.98 per 100,000 adults.

While the majority of published data have come from Europe, CADASIL has been observed on all continents.

A founder effect has been reported for Finnish individuals with CADASIL [Mykkanen et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with CADASIL, the following evaluations are recommended:

• Neurologic evaluation
• Psychometrics with particular attention to executive function
• Standard brain MRI (FLAIR sequence)
• Genetics consultation

Treatment of Manifestations

There is no treatment of proven efficacy for CADASIL. Antiplatelet treatment is frequently used, but not proven effective in CADASIL.

Migraine should be treated symptomatically and prophylactically, depending on the frequency of manifestations. There is no evidence that triptans and ergot derivatives should be avoided, although triptans may be preferable to ergot derivatives for treatment of migraine attacks.

Co-occurrence of hypertension, diabetes, and hypercholesterolemia should be treated.

Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families.

Further discussion of medical management options for individuals with CADASIL was published by del Río-Espínola et al [2009].

No specific support group exists for individuals with CADASIL, but information relevant to Huntington disease and Alzheimer disease can well be applied to CADASIL.

Surveillance

The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of the patients and their care givers.

Agents/Circumstances to Avoid

Angiography and anticoagulants are contraindicated in CADASIL as they may provoke cerebrovascular accidents [Lesnik Oberstein et al 2001].

Smoking increases the risk of stroke in individuals with CADASIL and should be avoided [Singhal et al 2004].

Thrombolytic therapy (intravenous thrombolysis) is contraindicated because of the presumed increased risk for cerebral hemorrhage [expert opinion].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although no formal studies have been performed, there is no evidence from clinical practice that fetuses affected with CADASIL are at an increased risk for intrauterine complications or complications during/after delivery.

Women with a NOTCH3 mutation have been described to be at an increased risk for neurologic events in pregnancy and during and shortly after delivery (puerperium) [Roine et al 2005]. However, it should be noted that this study was performed retrospectively. In the authors’ experience, most women with CADASIL have an uncomplicated pregnancy and delivery, but transient neurologic events are sometimes reported (mostly consistent with migraine aura) [Lesnik Oberstein, unpublished observation based on clinical practice].

Therapies Under Investigation

A double-blind placebo-controlled trial evaluating the efficacy and safety of donepezil HCL in individuals with CADASIL who have cognitive impairment revealed that donepezil had no effect on the primary (cognitive) endpoint, the V-ADAS-cog score. Improvements were noted however on several secondary measures of executive function; the clinical relevance of these findings is not clear [Dichgans et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Cross-sectional and longitudinal studies suggest that disease progression is faster in individuals with CADASIL who have increased blood pressure [Peters et al 2004, Holtmannspotter et al 2005, Peters et al 2006]. However, no controlled data are available regarding the effect of antihypertensive treatment on disease progression.

Based on experience with stroke in general, many neurologists prescribe salicylates. Whether these are of any efficacy in preventing stroke in individuals with CADASIL has not been studied.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

CADASIL is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with CADASIL have an affected parent, although occasionally the family history is reported to be negative.
• A proband with CADASIL may have the disorder as the result of a new gene mutation. One such mutation has been reported [Joutel et al 2000].
• The recommended evaluation of apparently asymptomatic parents of an individual with CADASIL who has a known NOTCH3 mutation is molecular genetic testing. Note that genetic testing of asymptomatic parents should be performed in the context of formal genetic counseling as such testing constitutes predictive testing.
• In a proband with no known mutation and no family history of CADASIL, neuroimaging and/or skin biopsy of parents may be considered. If the parents are deceased, review of available neuroimaging and medical records may provide sufficient information to retrospectively diagnose an affected parent.
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed (see Note below).
• Razvi et al [2005a] documented that a false negative family history was common for individuals presenting with features of CADASIL. They conclude that restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees.
• Homozygous mutations in NOTCH3 have been described in individuals with CADASIL [Tuominen et al 2001, Liem et al 2008b]. In such cases, both parents of a proband may have a NOTCH3 mutation.

Note: Although most individuals diagnosed with CADASIL have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to sibs is 50%.
• If the proband is homozygous for a NOTCH3 mutation and both parents are heterozygous, the risk to the sibs of the proband of having at least one NOTCH3 mutation is 75%.
• If the disease-causing mutation cannot be detected in the DNA extracted from leukocytes of either parent, the risk to sibs is reduced to almost zero, as the proband probably has a de novo mutation. Germline mosaicism is theoretically possible but has not been reported to date.

Offspring of a proband

• Every child of an individual with a NOTCH3 mutation has a 50% chance of inheriting the mutation.
• Offspring of a proband who is homozygous or compound heterozygous for NOTCH3 mutations have a 100% chance of inheriting one of the mutations.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults is available using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Routine testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis.

It is appropriate to follow the guidelines published for presymptomatic testing for Huntington disease. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations, including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of CADASIL, and the possible impact of positive and negative test results are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing for at-risk asymptomatic individuals younger than age 18 years. Consensus holds that testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Genetic testing is always indicated in affected or symptomatic individuals in a family with established CADASIL regardless of age.

For more information, see the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing mutation of an affected family member must be identified before prenatal testing can be performed. Prenatal diagnosis of CADASIL has been reported [Milunsky et al 2005].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as CADASIL are not common. Differences in perspectives may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 6-22-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available online. 1995. Accessed 6-22-12.

Literature Cited

1. Boon EMJ, Pont MJ, van Heusden D, Vollebregt MJ, Lakeman P, Elting M, Lesnik Oberstein SAMJ, Ginjaar HB. Detection of large deletions/duplications in NOTCH3 in CADASIL patients using MLPA. Abstract 10476. Honolulu, HI: American Society of Human Genetics Annual Meeting. 2009.
2. del Río-Espínola A, Mendióroz M, Domingues-Montanari S, Pozo-Rosich P, Solé E, Fernández-Morales J, Fernández-Cadenas I, Montaner J. CADASIL management or what to do when there is little one can do. Expert Rev Neurother. 2009;9:197–210. [PubMed: 19210195]
3. Amberla K, Waljas M, Tuominen S, Almkvist O, Poyhonen M, Tuisku S, Kalimo H, Viitanen M. Insidious cognitive decline in CADASIL. Stroke. 2004;35:1598–602. [PubMed: 15143298]
4. Auer DP, Putz B, Gossl C, Elbel G, Gasser T, Dichgans M. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology. 2001;218:443–51. [PubMed: 11161160]
5. Belin de Chantemèle EJ, Retailleau K, Pinaud F, Vessières E, Bocquet A, Guihot AL, Lemaire B, Domenga V, Baufreton C, Loufrani L, Joutel A, Henrion D. Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries. Arterioscler Thromb Vasc Biol. 2008;28:2216–24. [PMC free article: PMC2658748] [PubMed: 18818417]
6. Bruening R, Dichgans M, Berchtenbreiter C, Yousry T, Seelos KC, Wu RH, Mayer M, Brix G, Reiser M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: decrease in regional cerebral blood volume in hyperintense subcortical lesions inversely correlates with disability and cognitive performance. AJNR Am J Neuroradiol. 2001;22:1268–74. [PubMed: 11498413]
7. Chabriat H, Levy C, Taillia H, Iba-Zizen MT, Vahedi K, Joutel A, Tournier-Lasserve E, Bousser MG. Patterns of MRI lesions in CADASIL. Neurology. 1998;51:452–7. [PubMed: 9710018]
8. Chabriat H, Mrissa R, Levy C, Vahedi K, Taillia H, Iba-Zizen MT, Joutel A, Tournier-Lasserve E, Bousser MG. Brain stem MRI signal abnormalities in CADASIL. Stroke. 1999;30:457–9. [PubMed: 9933287]
9. Chabriat H, Pappata S, Ostergaard L, Clark CA, Pachot-Clouard M, Vahedi K, Jobert A, Le Bihan D, Bousser MG. Cerebral hemodynamics in CADASIL before and after acetazolamide challenge assessed with MRI bolus tracking. Stroke. 2000;31:1904–12. [PubMed: 10926955]
10. Cumurciuc R, Henry P, Gobron C, Vicaut E, Bousser MG, Chabriat H, Vahedi K. Electrocardiogram in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients without any clinical evidence of coronary artery disease: a case-control study. Stroke. 2006;37:1100–2. [PubMed: 16514092]
11. Cumurciuc R, Massin P, Paques M, Krisovic V, Gaudric A, Bousser MG, Chabriat H. Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry. 2004;75:1058–60. [PMC free article: PMC1739116] [PubMed: 15201374]
12. del Río-Espínola A, Mendióroz M, Domingues-Montanari S, Pozo-Rosich P, Solé E, Fernández-Morales J, Fernández-Cadenas I, Montaner J. CADASIL management or what to do when there is little one can do. Expert Rev Neurother. 2009;9:197–210. [PubMed: 19210195]
13. Dichgans M. Cognition in CADASIL. Stroke. 2009;40:S45–7. [PubMed: 19064778]
14. Dichgans M, Filippi M, Bruning R, Iannucci G, Berchtenbreiter C, Minicucci L, Uttner I, Crispin A, Ludwig H, Gasser T, Yousry TA. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999;52:1361–7. [PubMed: 10227618]
15. Dichgans M, Herzog J, Gasser T. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Neurology. 2001;57:1714–7. [PubMed: 11706120]
16. Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke. 2002;33:67–71. [PubMed: 11779891]
17. Dichgans M, Markus HS, Salloway S, Verkkoniemi A, Moline M, Wang Q, Posner H, Chabriat HS. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol. 2008;7:310–8. [PubMed: 18296124]
18. Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol. 1998;44:731–9. [PubMed: 9818928]
19. Federico A, Bianchi S, Dotti MT. The spectrum of mutations for CADASIL diagnosis. Neurol Sci. 2005;26:117–24. [PubMed: 15995828]
20. Feuerhake F, Volk B, Ostertag CB, Jungling FD, Kassubek J, Orszagh M, Dichgans M. Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL. Acta Neuropathol (Berl). 2002;103:188–92. [PubMed: 11810186]
21. Gladstone JP, Dodick DW. Migraine and cerebral white matter lesions: when to suspect cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neurologist. 2005;11:19–29. [PubMed: 15631641]
22. Goebel HH, Meyermann R, Rosin R, Schlote W. Characteristic morphologic manifestation of CADASIL, cerebral autosomal- dominant arteriopathy with subcortical infarcts and leukoencephalopathy, in skeletal muscle and skin. Muscle Nerve. 1997;20:625–7. [PubMed: 9140375]
23. Haritoglou C, Rudolph G, Hoops JP, Opherk C, Kampik A, Dichgans M. Retinal vascular abnormalities in CADASIL. Neurology. 2004;62:1202–5. [PubMed: 15079027]
24. Holtmannspotter M, Peters N, Opherk C, Martin D, Herzog J, Bruckmann H, Samann P, Gschwendtner A, Dichgans M. Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study. Stroke. 2005;36:2559–65. [PubMed: 16269644]
25. Joutel A, Tournier-Lasserve E. Notch signalling pathway and human diseases. Semin Cell Dev Biol. 1998;9:619–25. [PubMed: 10075489]
26. Joutel A, Dodick DD, Parisi JE, Cecillon M, Tournier-Lasserve E, Bousser MG. De novo mutation in the Notch3 gene causing CADASIL. Ann Neurol. 2000;47:388–91. [PubMed: 10716263]
27. Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001;358:2049–51. [PubMed: 11755616]
28. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511–5. [PubMed: 9388399]
29. Kim Y, Choi EJ, Choi CG, Kim G, Choi JH, Yoo HW, Kim JS. Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Neurology. 2006;66:1511–6. [PubMed: 16717210]
30. Lesnik Oberstein SA, Jukema JW, Van Duinen SG, Macfarlane PW, van Houwelingen HC, Breuning MH, Ferrari MD, Haan J. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Medicine (Baltimore). 2003;82:251–6. [PubMed: 12861102]
31. Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J. Cerebral microbleeds in CADASIL. Neurology. 2001;57:1066–70. [PubMed: 11571335]
32. Leyhe T, Wiendl H, Buchkremer G, Wormstall H. CADASIL: underdiagnosed in psychiatric patients? Acta Psychiatr Scand. 2005;111:392–6. [PubMed: 15819734]
33. Liem MK, Lesnik Oberstein SA, Haan J, van der Neut IL, van den Boom R, Ferrari MD, van Buchem MA, van der Grond J. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: progression of MR abnormalities in prospective 7-year follow-up study. Radiology. 2008a;249:964–71. [PubMed: 18840792]
34. Liem MK, Lesnik Oberstein SA, Vollebregt MJ, Middelkoop HA, van der Grond J, Helderman-van den Enden AT. Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms: a family report. J Neurol. 2008b;255:1978–80. [PubMed: 19153638]
35. Louvi A, Arboleda-Velasquez JF, Artavanis-Tsakonas S. CADASIL: a critical look at a Notch disease. Dev Neurosci. 2006;28:5–12. [PubMed: 16508299]
36. Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF. Diagnostic strategies in CADASIL. Neurology. 2002;59:1134–8. [PubMed: 12395806]
37. Milunsky A, Konialis C, Shim SH, Maher TA, Spengos K, Ito M, Pangalos C. The prenatal diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by mutation analysis. Prenat Diagn. 2005;25:1057–8. [PubMed: 16302168]
38. Mykkanen K, Savontaus ML, Juvonen V, Sistonen P, Tuisku S, Tuominen S, Penttinen M, Lundkvist J, Viitanen M, Kalimo H, Poyhonen M. Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet. 2004;12:813–9. [PubMed: 15378071]
39. Nakamura T, Watanabe H, Hirayama M, Inukai A, Kabasawa H, Matsubara M, Mitake S, Nakamura M, Ando Y, Uchino M, Sobue G. CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci. 2005;238:87–91. [PubMed: 16111703]
40. O'Sullivan M, Jarosz JM, Martin RJ, Deasy N, Powell JF, Markus HS. MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL. Neurology. 2001;56:628–34. [PubMed: 11245715]
41. Oberstein SAJ. Diagnostic strategies in CADASIL. Neurology. 2003;60:2020. [PubMed: 14710716]
42. Oberstein SA, Ferrari MD, Bakker E, van Gestel J, Kneppers AL, Frants RR, Breuning MH, Haan J. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999;52:1913–5. [PubMed: 10371548]
43. Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004;127:2533–9. [PubMed: 15364702]
44. Park JT, Shih IeM, Wang TL. Identification of Pbx1, a potential oncogene, as a Notch3 target gene in ovarian cancer. Cancer Res. 2008;68:8852–60. [PMC free article: PMC2636690] [PubMed: 18974129]
45. Peters N, Herzog J, Opherk C, Dichgans M. A two-year clinical follow-up study in 80 CADASIL subjects: progression patterns and implications for clinical trials. Stroke. 2004;35:1603–8. [PubMed: 15155961]
46. Peters N, Holtmannspotter M, Opherk C, Gschwendtner A, Herzog J, Samann P, Dichgans M. Brain volume changes in CADASIL: a serial MRI study in pure subcortical ischemic vascular disease. Neurology. 2006;66:1517–22. [PubMed: 16717211]
47. Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005a;62:1091–4. [PubMed: 16009764]
48. Peters N, Opherk C, Danek A, Ballard C, Herzog J, Dichgans M. The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia. Am J Psychiatry. 2005b;162:2078–85. [PubMed: 16263847]
49. Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M. Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke. 2001;32:17–21. [PubMed: 11136908]
50. Razvi SS, Davidson R, Bone I, Muir KW. Is inadequate family history a barrier to diagnosis in CADASIL? Acta Neurol Scand. 2005a;112:323–6. [PubMed: 16218915]
51. Razvi SS, Davidson R, Bone I, Muir KW. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry. 2005b;76:739–41. [PMC free article: PMC1739620] [PubMed: 15834040]
52. Roine S, Poyhonen M, Timonen S, Tuisku S, Marttila R, Sulkava R, Kalimo H, Viitanen M. Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology. 2005;64:1441–3. [PubMed: 15851739]
53. Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 1997;56:947–64. [PubMed: 9291937]
54. Scheid R, Heinritz W, Leyhe T, Thal DR, Schober R, Strenge S, von Cramon DY, Froster UG. Cysteine-sparing notch3 mutations: cadasil or cadasil variants? Neurology. 2008;71:774–6. [PubMed: 18765654]
55. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS. "CADASIL coma": an underdiagnosed acute encephalopathy. J Neurol Neurosurg Psychiatry. 2003;74:249–52. [PMC free article: PMC1738281] [PubMed: 12531961]
56. Schroder JM, Zuchner S, Dichgans M, Nagy Z, Molnar MJ. Peripheral nerve and skeletal muscle involvement in CADASIL. Acta Neuropathol (Berl). 2005;110:587–99. [PubMed: 16328531]
57. Schultz A, Santoianni R, Hewan-Lowe K. Vasculopathic changes of CADASIL can be focal in skin biopsies. Ultrastruct Pathol. 1999;23:241–7. [PubMed: 10503743]
58. Sicurelli F, Dotti MT, De Stefano N, Malandrini A, Mondelli M, Bianchi S, Federico A. Peripheral neuropathy in CADASIL. J Neurol. 2005;252:1206–9. [PubMed: 15827866]
59. Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031–8. [PubMed: 15229130]
60. Singhal S, Rich P, Markus HS. The spatial distribution of MR imaging abnormalities in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and their relationship to age and clinical features. AJNR Am J Neuroradiol. 2005;26:2481–7. [PubMed: 16286388]
61. Tuominen S, Juvonen V, Amberla K, Jolma T, Rinne JO, Tuisku S, Kurki T, Marttila R, Poyhonen M, Savontaus ML, Viitanen M, Kalimo H. Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke. 2001;32:1767–74. [PubMed: 11486103]
62. van den Boom R, Lesnik Oberstein SA, Spilt A, Behloul F, Ferrari MD, Haan J, Westendorp RG, van Buchem MA. Cerebral hemodynamics and white matter hyperintensities in CADASIL. J Cereb Blood Flow Metab. 2003;23:599–604. [PubMed: 12771575]
63. van den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology. 2002;224:791–6. [PubMed: 12202716]
64. Williamson EE, Chukwudelunzu FE, Meschia JF, Witte RJ, Dickson DW, Cohen MD. Distinguishing primary angiitis of the central nervous system from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: the importance of family history. Arthritis Rheum. 1999;42:2243–8. [PubMed: 10524700]
65. Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, Shimizu K, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Ohwada S, Tatsuta K, Inoue J, Semba K, Watanabe S. NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 2008;68:1881–8. [PubMed: 18339869]
66. Yanagawa S, Ito N, Arima K, Ikeda S. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. Neurology. 2002;58:817–20. [PubMed: 11889251]

Suggested Reading

1. Bowler JV. Vascular cognitive impairment. J Neurol Neurosurg Psychiatry. 2005;76 Suppl 5:v35–44. [PMC free article: PMC1765709] [PubMed: 16291920]
2. Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T. The pathogenesis of CADASIL: an update. J Neurol Sci. 2004;226:35–9. [PubMed: 15537516]
3. Lesnik Oberstein SA, Haan J. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Panminerva Med. 2004;46:265–76. [PubMed: 15876982]

Author History

Elles MJ Boon, PhD (2006-present)
Martijn H Breuning, MD, PhD; Leiden University Medical Center (2000-2006)
Martin Dichgans, MD, PhD; Ludwig-Maximilians-Universität München (2006-2012)
J Haan, MD, PhD; Leiden University Medical Center (2000-2006)
Saskia AJ Lesnik Oberstein, MD, PhD (2000-present)
Gisela M Terwindt, MD, PhD (2012-present)

Revision History

• 28 June 2012 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 21 November 2006 (me) Comprehensive update posted to live Web site
• 2 August 2004 (me) Comprehensive update posted to live Web site
• 23 August 2002 (me) Comprehensive update posted to live Web site
• 15 March 2000 (pb) Review posted to live Web site
• January 2000 (slo) Original submission